Dihydro-m-thiazine-delta-3, 4 compounds and process for their preparation



United States Patent DHiYDRO-M-TI-IIAZINE-A-BM- COL [POUNDS AND PROCESS FOR THEIR PREPARATION Friedrich Asinger and Max ,Thiel, Leuna, and Walter Htiringklee, Halle, Germany, assignors to VEB Leuna- -Werke Walter Ulbricht, Leuna, Germany No Drawing. Filed Aug. 22,- 1957, Ser. No. 679,773 Claims priority, application Germany Oct. 6, 19 56 27 Claims. Cl. 260-243) s s; s s

A method for the preparation of compounds containing the nucleus (2) above hasnot beendescribed in the literature. g

It is an object of the present invention to provide a process for the preparation of dihydro-1,3-th iazineshaving the nucleus of Formula 2 above.

It is also an object of this invention to provide substituted products of Formula 2 above Other and more detailed objects of this invention will be apparent from the following description and claims. It; has been found. that -dihydro-m-thiazine-A-3,4 compounds of this invention may be prepared simply andeconomically by the reaction of a 'B-mercaptoketone," an

organo oxo compound (e.g. aldehyde or ketone) and ammonia or'an ammonium salt of a weak acid (c.g. ammonium carbonate, ammonium acetate,i etc); "The reaction, is exothermic and commences on the mixingof the reactants in the reaction vessel at room temperature. .Injsome'cases it is advantageous to slightly heat'the reaction mixture to initiate the reaction which then becomes self-sustaining by the heat evolved during the, reaction. In some cases the yield of the product is increased by cooling thereacti on mixture to about C. In general the reaction may be carried out within the temperature range of about 100 C.*to' about -15 C. The yields'obtained'are almost quantitative.

-The organo oxo reactants-that maybe employed in' the process of this invention are quite varied. They may be aliphatic, alicyclic, heterocyclic, arylor aralkyl 2,946,788 Patented July 26, 1960 ice More particularly the present invention is directed to the preparation of compounds of general formula:

formula ketones, as well as aliphatic, alicyclic, aromatic, 'lieterocyclic or aralkylaldehydes; Theketonesthat are useful wherein R and R are as defined above. I 1 7 It is also withinthe scope ofthe-present invention to wherein R is a monovalent radical selected from the' class consisting of ,alkyl, cycloalkyland aryl radical; and R is selected from the class consisting of H, alkyl, cyclo alkyl, aryl and aralkyl radicals. It is to be understood that the R and R groups in Formula 5 above need not represent the same group throughout but may have any of the values included the definition. When R or R are alkyl radicals in Formula 5, they represent any 'alkyl group. By way of illustration may be mentioned the alkyl groups having from 1 to 20 carbon atoms includingthe methyl, ethyl, propyl, isopropyl, butyl, tent, buty1, -i sobuty1,-.amyl, hexyl, 2-ethylhexyl, heptyl, octyl, isooctyl, nonyl, decyl, undecyl, dodecyl, tn'decyl, tetradecyl, pentadecyl, hexadecyl and eicosyl. In a preferred form [of this invention the alkyl. groups represented by R and; R are lower alkyl groups and, more particularly, alkyl groups having from '.1 to 8 carbon atoms in the alkyl groups. The cycloalkyl radicals included within the definitionof Rand R are, ,preferably, those having from 4to 12 carbon atoms in-the ring'structure.

Thearyl'and aralkyl radicals represented by R and R above are monovalent carbocyclic aryl or aralkyl radicals, and more particularly, those having from 1 to 3 rings in the. aryl -ring.- Byway of illustration may be mentioned the. phenyl, naphthyl, anthracyl, benzyl, phenyl ethyl, phenylpropyl, tolyl, xylyl,.ethylpheny1,

propylphenyl, hydroxyphenyl, hydroxynaphthyl, biphenyl} terphenyl, tetralinyl radicals.

radical, e .g., phenyl, monohydroxyphenyl, alkyl substituted phenyl, and monohydroxy alkyl substituted .phenyl I radicals;

Similarly, the preferred aralkyl radicals are the monovalent monocyclic aralkyl radicals, e.g. ,phen yl-. alkylene, alkyl substituted phenylalkylene, monohydroxy phenylalkylene, and monohydroxy alkyl substituted phenylalkylene radicals. These may be described by the RIIIII bon atoms in the alkylene chain and R'" and Rf are H, alkyl or OH.

The reactioninvolvedin the. present case may be illus V trated by the io'llovving equation; v

form the fl-mercaptoketone reactant in the reaction mixture, as distinguished from the addition of the preformed B-mercaptoketone to the reaction mixture. This may be accomplished by introducing a mixture of H 5 and ammonia into, preferably, an equilmolar mixtureof an 0a,]3- unsaturated ketone and an aldehyde or ketone. The H 8 reacts at the double bond of the afi-unsa-turated ketone and forms the B-mercaptoketone. The fl mercaptoktoiie so formed their 'r'eactsjwith theald d'e or ketone and ammonia *in 'accbrdanee with Equation '6' above. This overall reaction may be described by the following equation:

7 R R1 l C==O R\ R-C 11/ E s E l! +ms+1 fm+o c li -('3 V wherein R and R have the same signific'ance ascribed to above In place of the ammonia shown in Equation 7 an ammonium salt of a weak acid may be employed, eig. ammonium carbonate, ammonium acetate,

ere. V

The present invention rovides a articulafly i'm ie method of converting acetone into a eihydro-m-thiaiifie- A-3,4 compound. 'Iheiritro'duction of His and am en'ifa into acetone converts the acetone to 2,2,4,'6,6-penta methyl-'dihydrom-thiaZine-A-BA. It thought that in this ease mesi'tyl @636 (the e,}3'-uns aturated ketone'fis presentv invention, and it will be understood that the in vfltion'is not lin'rited thereto:

EXAMPLE 1 4,6,6-triniethgil-dihydro-m-thidZihe A-3,4 Ammonia is introduced with stirring into 500 of a formaldehyde solution of 40% strength, which is continuously cooled to -l0 At the-same time, 132 g. of Z-methyl-Zmercaptopentanone-4 is'added dropwise in the course of 2 hours. v M p v I which ammonia is continuously supplied, :th'ereac'tion' is completed. The dihydrothiazine obtained is extracted with ether and is distilled after removal ofifthe B.P., 74-75" C./ 12mm. Hg picrate F., 195 C.; yield, 95%. p g

Instead of the formaldehyde solution, an aqueous solution of urotropine may b'e'us'edintliis example.

EXAMPLE [I 2-ethyl-2,4,6,6-tetramethyl-dihydr0-m-rhiazine-A-3,4

360 g. of butanone are admiiredwith 20 cm. of water and cooled to C. Ammonia is introduced into the mixture w-hile stirring and in the course of 2 hours 1 mole of 2methyl-2mercaptopentanone-4 is added dropwise. Thereafter ammonia is int'roduced 'forfurtliei- 2 hours; The working upiseifee'ted as iir-Enample'I.

After another hour, during n-propanol the dihydrothiazine is obtained in the form of white crystals. F., 136 0.; yield, 100%.

EXAMPLE 1V 4,6,6-trimethyl-2-0-hydroxylphenyl-dihydro-mthiazine-A-3,4

hydrothi'azine is obtained in crystalline form and is re- The reaction is completed after 3 hours.

crystallized from n-propanol. F., 136 C.; yield, 97%.

' EXAMPLE v 2-propyl-4,6-dimeihyl-dihjzdro-rh-thidZine-AJ,4

84 g. of methyl properiyl' ketone and 144 g. of butyraldehyde are mixed while cooling to 10 C. and admixed with 10 Chi? of water. Then ammonia. and H S in a volume ratio of 2:1 are introduced with stirring. The.

reaction mixture should be kept constantly at 10 C. 200 cm. of 10% NaOH solution are added and then the reaction mixture is extracted with ether. The etheral "extract solution is then washed with water, dried with sulfate and finally concentrated. Fractionated distillati'oii of the residue yields the dihydrothiazine in "84% yield. "B.-P. '97-'99 12mm. Hg.

EXAMPLE W I 2,2,4,6,6-pentamethyl-dihydi-o-m-thiazine-A-3,4

98 g. of mesityloxide are mixed with 580 g. of acetone and 20 cm. of water are added thereto. Ammonia and H S (volume ratio 2:1) are introduced into the solution while stirring. The temperature in the reaction vessel rises to 42 C. After 4 hours the reaction is completed.

200 cm of Water are added and ether extraction :is per formed.

The ether solution is dried with Na S0 andvyields'the dihydrothiazine in yield. B-.P. 69-72/'12- mm.- Hg; picrate F., 183 0.

EXAMPLE VII 2,2,4-trimethyl-fi-pheriyl-dihydro-thiazine-A-3,4

146 g. of benzalacetone are dissolved in 580 g.'6f acetone and 20 cm. of water are added thereto. stirring, ammonia and H 8 are introduced into tzlieskflii tion in a volume ratio of 2: 1.

p p I The reaction semiarmediately and the temperature rises to 40 C. Thei'action is completed-after-about4 hours. cm'. '-oi-40%' NaOH solution are added. Thenthe solution is taken-up rises to about 45 f" C. The reaction is completed: after about 3 hours. The reactionmixture' is then dilutedwith 200 cm? of water and 100 cm. of'40% NaOH solution are added, whereby an oily layer separates. The layer is taken up in ether. Working up as in Example -2. RR.

69-72 C./ 12 mm. Hg; picrate F., 183 C.; yield, 30%.

'EXAMPLEIX p 2,2,4,6,6-pentamefhyl-dihydro m-thidzine-A-JQJ HgS is' introduced while stirring into a mixeneeras g; df-mesitywxiae, 2'40 ofacetofie, 154 g. of "611i acetate ana' zso cm? of water;

Upon distillation of the fesidue'the The reaction is 1 pleted after 3 hours. After addition of 200 cm. of NaOI-I' formula 5 s Qn..(4 c ncen at on) th is ret eat with ether. The ether solution is washed with water-and dried with sodium sulfate. Upon distillation the dihydrothiazine is obtained in 75% yield B.P. 69-72 C./12

mm. Hg; picrate F., 183 C, a

The dihydro-m-thiazine-A-3',4 compounds have a strong physiological activity andjniay be used in the synthesis of therapeutic compounds; They are also useful as accelerators in thevulcanization of'rubber, as pesticides, as wood preservatives, I as weed killers, "as rust inhibitors and for the protection againstaging. While the invention has been described' 'th reference to various examples and embodiments, it-.will'be" appareht tothose skilled in the art'that various modifications'may be made; and equivalents substituted therefor, without departing from the principles and true natureiof the presentinvention. f What is claimed is: 1. A process for the preparation .of 2,2,4,6,6-pentamethyl-dihydro'-m-thiazine-A-3,4 which comprises, reacting acetone with 'a mixture of. H 8 and a 'compound ammonia "and am wherein R is lower alkyl.

3. As a composition of matter, a compound of general R on, N R

wherein R is lower alkyl.

4. As a composition of matter, a compound of general formula 3 n on, N R \5 5/ wherein R is lower alkyl and R is monocarbocyclic aryl. 5. As a composition of matter, a compound of general formula n on, N n wherein R is lower alkyl.

6. As a composition of matter, a compound of general formula B AH (5 wherein R is lower alkyl and R is monocarbocyclic aryl.

7. A process according to claim 16, wherein the ammonium salt of said weak acid is ammonium carbonate. 8. A process according to claim 7 wherein the react-ion by volume into acetone and allowing saidv mixture to dihydro-m-thiazine-A-3,4.

'hydroxyphenyl-dihydro m-thiazine A-it,4.

react to, produce the desired compound. p

10.1As a composition of matter: 4,6,6 trimethyl- 11. As a composition of matter: l,6;6trimethyl- 2i-o-.

12. As a composition of matter: '2-ethyl 2 ,4,6,6-tet'ramethyl-dihydro-m-thiazine-A-3,4. V p

' 13. As a composition of matter: 2-propyl-4,6-dimethyldihydro-ni-thiazin-A-BA. w 7

14. As 'a' composition of matter: 2,2,4,6,6-penta methyl-dihydro-m-thiazine-A-3,4. E 15. As a composition of matter: 2,2,4-trimethyl-6- phenyl-dihydro-m-thiazine- A-B,4.

16. A process for the preparation of dihydro-m-thiazine-A-3,4 compounds which comprises reacting a panercaptoketone of formula r r R] R (5:0 Q R-Jl-SH with an organo oxo carbonyl compound of formula and a nitrogen compound selected from the class consisting of ammonia and an ammonium salt of a weak acid, wherein R is a monovalent radical selected from the class consisting of alkyl, cycloalkyl, monocarbocyclic aryl and monocarbocyclic aralkyl, and R is a radical selected from the group consisting of hydrogen, alkyl, cycloalkyl, monovalent monocarbocyclic aryl and monovalent monocarbocyclic aralkyl, said alkyl radicals having from 1 to 20 carbon atoms in the alkyl chain, and said cycloalkyl radicals having from 4 to 12 carbon atoms in the cycloalkyl ring.

17. A process for the preparation of dihydro-m-thiazine-A-3,4 compounds which comprises reacting an a,fl-unsaturated ketone of formula with an organo oxo carbonyl compound of formula ammonia and H 8, said ammonia and H 8 being employed in the proportion of volume of 1:1, wherein R' is a radical selected from the group consisting of alkyl,

cycloalkyl, monovalent monocarbocyclic aryl and monovalent monocarbocyclic aralkyl, and R is a radical selected from the group consisting of hydrogen, alkyl,

19. A process 'for the preparation of l-ethylilfi fifitetramethyl-dihydro-m-thiazine1A 3,4 which comprises ,re-

acting hutanon w h am q and fl Y -Z-m QaPE pentanone-4.

r20. Aprqcess fortthe preparation of 4,6;6-trirnethyl- Z-o-hy'droxyphenyIQdihydrO-ni thiazine-A-3,4 which comprises treactinglammonia with salicylaldehyde' and Z-methyl 2-mercaptopentanone-4.

2;1. Aaprocess. for the preparation .of s4,6,6-trimethyl- 2-o-hydroxylphenyl dihydi o-m-thiaZine-AaS,4 which coinprise rea tin sal y a dehy w th 2-mcthy e ap pentanone-4 and ammonium'carbonate.

'22. process 'lfOI the preparation of ;2-propy14,6- dimethyl-dihydro-m-thiazine-A-3,4 which :comprises reacting methyl xpropenyl :ketone with hutyraldehyde, -am monia and H 8.

"23. process for the preparation of '2',2,4,6;6-pentamethyl-'dihydro-m-thiazine-A3 4 which comprises reactiDgiIlSitYlOXidC with-ammonia, acetone anc1"H S.

"24. A process for the preparation of -2;2,4-tri1nethyl- -phenyl-dihydro-m-thiazine-A-3,4 which comprises reacting bcnzalacetone with acetone, ammonia and H 8.

25. A process for the preparation of 2,2,4,6,6-pentamethyl-dihydro-m-thiazine-A-3 4 which comprises reacting H 8 with mesityloxidc, acetone and ammonium acetate.

'26. a *co position i matter, a compound of :R' R 5 "R C/ :R-c (l- R: R ta wherein :R' -;a smonoyalent ;-rad,ical selected. "from the class consisting .;;of ,alkyl, cycloalkyl, monocarbocyclic anyl zand monocanhocyclic .ara1kyl, and -R is a radical selected :fromE- the .group1;consisting"of hydrogen, alkyl, cycloalkyl, 'monoyalentmonocarbocyclic aryl and momovalent monocarbocyclic .aralkyl, said alkyl radicals having'iromwzluto 20:.carbonatoms :the .alkyl chain, and said cycloalkyl radicals having from 4 to :12 carbon atoms in the cycloalkyl ring. i

27. A- procss#according'to claim 16 "wherein the fi-mercaptoketone reactant is formcd in- -situ in the reaction mixture, z'through the condensation i. of acetone 10 form :athe =;.'a-,;8sunsati1rated zketone,v and 'ithe "subsequent reaction of the so formedaafi unsaturated ketone with H s ato, form 1116 aflsmercaptoketone reactant.

References Cited in the file of this patent Pinkus: Ber. der Deutsche Chem. GeselL, vol. 26 (1893), pp. 1077-1078. 

26. AS A COMPOSITION OF MATTER, A COMPOUND OF FORMULA 